Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. Alcohol intake remains the most important cause of liver cirrhosis in Western countries. Alcoholic liver disease can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. ATRA administration can prevent and reverse the course of liver fibrosis in animal models. Several studies have shown that inhibition of certain cytochrome P450 enzymes in vivo can boost endogenous ATRA levels and result in retinoid-like activity in dermatological and oncological animal models. The cytochrome P450 enzyme retinoic acid 4-hydroxylase is thought to be the key enzyme involved ATRA catabolism. In our preliminary data, we show that an inhibitor of retinoic acid 4-hydroxylase shows activity in a mouse model of TAA-induced liver fibrosis in mice, thus establishing a novel proof of concept for their potential use as therapeutics for liver fibrosis. Our long-term goal is the development of small molecule inhibitors of retinoic acid 4-hydroxylase as potential therapeutics for alcoholic liver disease. The objective of this application is to identify such inhibitors and evaluate them in two clinically relevant animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver caused by sustained immoderate alcohol consumption. Over time it frequently progresses to cirrhosis, an end- stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There is no therapeutic that shows consistent improvement in the course of alcoholic liver damage and there remains a major unmet medical need for effective therapies. There is a significant body of evidence implicating a requirement for All Trans Retinoic Acid (ATRA) for normal liver function and in liver regeneration. We intend to develop of small molecule inhibitors of retinoic acid 4- hydroxylase that can elevate the body's ATRA levels as a potential therapeutic for alcoholic liver disease.